Phosphodiesterase-5 inhibitor benzodioxole-derived gentiobioside as well as synthesis and application thereof

Abstract

The invention discloses gentiobioside derived from phosphodiesterase-5 inhibitor benzodioxole as well as synthesis and application of the gentiobioside, and belongs to the technical field of medicinal chemistry. The invention comprises compounds I, II and III, and pharmaceutically acceptable salts, solvates and prodrugs thereof. Wherein A is selected from CH and N, B is selected from C-R and N, and R is selected from H, CH3, F, Br, Cl, NO2, NH2, OCH3, CN and CF3; x is selected from the group consisting of O, NH, CH = CH and NH-CH2, Y is selected from the group consisting of O-CH2, CH2-CH2, CH = CH, CH = N, N = N and N = CH; for compound I, if A is N, B can only be C-R, and R is H; and for the compound II, according to the difference of X and Y, the rings in which XY is located can be divided into five-membered rings and six-membered rings, including aromatic rings and non-aromatic rings, and having no four-membered rings. These compounds are useful as phosphodiesterase-5 inhibitors for the treatment of sexual dysfunction. # imgabs0 #

Description

Technical Field

[0001] The invention relates to gentiobioside derived from a piperonyl ring of a phosphodiesterase-5 inhibitor and synthesis and application thereof, belonging to the technical field of pharmaceutical chemistry. Background Art

[0002] Penile erection is a hemodynamic event that depends on the balance of contraction and relaxation of the corpus cavernosum smooth muscle and the penile vascular system (Lerner et al, 1993, J. Urology, 149, 1256-1255). Cyclic guanosine monophosphate (cGMP) is the mediator that causes relaxation of corpus cavernosum smooth muscle cells.

[0003] Under sexual stimulation, nitric oxide synthase (NOS) in the penile nerve endings and vascular endothelial cells catalyzes the substrate L-arginine to synthesize nitric oxide (NO). NO activates guanylate cyclase, which converts guanosine triphosphate into cyclic guanosine monophosphate (cGMP), thereby activating cyclic guanosine monophosphate-dependent protein kinase, resulting in a decrease in calcium ion concentration in smooth muscle cells, causing the penis cavernous smooth muscle to relax and cause erection. Phosphodiesterase type 5 (PDE5) degrades cGMP into a product with no physiological activity, causing the penis to enter a flaccid state.

[0004] The compounds of the present invention inhibit the degradation of PDE5, resulting in the accumulation of cGMP, which relaxes the smooth muscle of the corpus cavernosum and leads to penile erection. Summary of the invention

[0005] The present invention discloses a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific type 5 phosphodiesterase (PDE5), which can be used to treat male dysfunction. Male dysfunction includes erectile dysfunction (ED), ejaculation disorders (such as impotence and premature ejaculation, loss of sexual desire, and inability to reach orgasm) or sexual desire disorders (such as poor sexual desire, lack of interest in sex, sexual arousal difficulties, and orgasm disorders). These compounds can also be used to treat pulmonary hypertension (increased pulmonary vascular resistance and elevated pulmonary artery pressure, PH), inhibit the increase in blood sugar caused by alloxan, and neuropsychiatric disorders.

[0006] The present invention provides compounds (I), (II) and (III):

[0007]

[0008] wherein A is selected from CH or N; B is selected from CR or N;

[0009] R is selected from H, CH3, F, Br, Cl, NO2, NH2, OCH3, CN and CF3;

[0010] X is selected from O, NH, CH=CH and NH-CH2,

[0011] Y is selected from O-CH2, CH2-CH2, CH=CH, CH=N, N=N and N=CH;

[0012] Also included are pharmaceutically acceptable salts, solvates and prodrugs thereof.

[0013] For compound I: if A is N, then B is CR and R is H;

[0014] For compound II: According to the difference between X and Y, the ring where XY is located can be divided into five-membered ring and six-membered ring, including aromatic ring and non-aromatic ring, and there is no four-membered ring.

[0015] For compounds I, II and III, their acid addition salts are pharmaceutically acceptable, and their salts can be precipitated more conveniently and are easier to purify by recrystallization.

[0016] Suitable acids are those which form non-toxic salts, examples being hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, hydrogenphosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate. (See WO2004 / 052372)

[0017] Pharmaceutically acceptable solvates of Compounds I, II and III include hydrates thereof.

[0018] Compounds I, II and III contain multiple chiral carbon atoms, most of which are introduced by chiral raw materials. In addition, diastereomers are also produced during the synthesis process. The separation of diastereomers can be achieved by step-by-step crystallization, automatic column flow through a chiral column or HPLC.

[0019] Compounds I, II and III of the present invention.

[0020] Wherein compound I is preferably: A is selected from CH or N, and B is selected from CR or N. Most preferably, A is N, B is CR and R is H;

[0021] Preferably, compound I, A is CH or N, B is CR or N. Preferably, A is CH, B is CR, and R is selected from H, CH3, Br, Cl, NH2 or OCH3. Preferably, A is CH, B is CR, and R is selected from H, CH3, NH2 or OCH3.

[0022] Preferably, compound II, X is selected from O, NH, CH=CH or NH-CH2, and Y is selected from O-CH2, CH=CH, CH=N or N=CH. Preferably, X is selected from O, NH or CH=CH, and Y is selected from O-CH2, CH=CH or N=CH. Most preferably, X is selected from NH or CH=CH, and Y is CH=CH or N=CH.

[0023] Compound III is also the most preferred compound.

[0024] The inventive compounds and salts thereof exemplified herein more preferably include:

[0025] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(4-fluorophenyl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol;

[0026] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(4-(trifluoromethyl)phenyl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol;

[0027] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(1H-indazol-6-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol;

[0028] (2R,3R,4S,5S,6R)-2-((1R)-1-(benzo[d][1,3]dioxol-5-yl)-2-((1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol;

[0029] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-((Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(1H-benzo[d]imidazol-6-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol;

[0030] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(naphthalen-2-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol;

[0031] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(naphthalen-1-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol;

[0032] Most preferred are:

[0033] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(1H-indazol-6-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol;

[0034] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(4-(trifluoromethyl)phenyl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol;

[0035] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(naphthalen-2-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol;

[0036] (2R,3R,4S,5S,6R)-2-((1R)-1-(benzo[d][1,3]dioxol-5-yl)-2-((1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol;

[0037] Compounds I, II and III were synthesized according to the following routes:

[0038] Synthesis of compound I: Aldehyde reacts with cyanide to obtain intermediate V, which is then reacted with gentiobiose at 50°C with acetyl chloride, and then reduced with borane or lithium aluminum hydride to obtain compound VI; finally, VI is subjected to reductive amination reaction with 1-(1,3-benzodioxol-5-yl)-2-propanone under weakly acidic conditions to obtain a diastereomeric mixture. The diastereomeric mixture needs to be chirally separated by fractional crystallization, automatic column flow through a chiral column, or HPLC.

[0039] The reaction route is shown below:

[0040]

[0041] Wherein: A is selected from CH or N, B is selected from CR or N, and R is selected from H, CH3, F, Br, Cl, NO2, NH2, OCH3, CN or CF3.

[0042] The synthesis of compound II, the reaction route is shown as follows:

[0043]

[0044] Wherein: X is selected from O, NH, CH=CH or NH-CH2, and Y is selected from O-CH2, CH2-CH2, CH=CH, CH=N, N=N or N=CH.

[0045] The intermediate VIII is obtained by reacting aldehyde with cyanide, and then reacting with gentiobiose at 50°C with acetyl chloride, and then reducing with borane or lithium aluminum hydride to obtain compound IX; finally, compound IX is subjected to reductive amination reaction with 1-(1,3-benzodioxol-5-yl)-2-propanone under weakly acidic conditions to obtain a diastereomeric mixture. The diastereomeric mixture needs to be chirally separated by fractional crystallization, automatic column flow through a chiral column, or HPLC.

[0046] The synthesis of compound III can refer to and be analogous to compounds I and II, and can be expressed by the chemical reaction equation as follows:

[0047]

[0048] All the above reactions and preparation of new raw materials are conventional, refer to the following examples and references. Those skilled in the art of synthesis are familiar with suitable methods for preparing compounds and post-treatment separation and purification schemes.

[0049] The compounds of the present invention are cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5) selective inhibitors, which achieve the purpose of erection by dilating the blood vessels supplying the corpus cavernosum, and do not cause sexual excitement by themselves, but can only take effect after sexual stimulation. However, the use of such compounds is associated with a large number of side effects, including headache, dizziness, facial flushing, rhinitis, eyelid swelling, slow reaction, and insensitivity, some of which may cause serious problems.

[0050] The compound of the present invention is an effective selective inhibitor of type 5 phosphodiesterase (PDE5), and at the same time reduces the toxic and side effects of existing drugs for treating sexual dysfunction.

[0051] The compounds of the present invention can treat male sexual dysfunction (effectively improving the quality and duration of erection, and increasing the success rate of sexual life for male patients with erectile dysfunction), ejaculation disorders (such as impotence and premature ejaculation, loss of sexual desire, and inability to reach orgasm), or sexual desire disorders (such as poor sexual desire, lack of interest in sex, difficulty in sexual arousal, and orgasm disorders).

[0052] The compound of the present invention can also be used to treat pulmonary hypertension (increased pulmonary vascular resistance and elevated pulmonary artery pressure, PH), inhibit the increase of blood sugar caused by alloxan, anticoagulation, emotional instability, and sleep disorders. Specific embodiments

[0053] The preparation of the compounds of the present invention is further described below by means of specific examples:

[0054] Example 1

[0055] (2R,3R,4S,5S,6R)-2-(2-amino-1-phenylethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0056] Amygdalin (5.0 g, 10.9 mmol) was dissolved in 20 mL of tetrahydrofuran and slowly added dropwise to a stirred suspension of tetrahydrofuran / LiAlH4 (1.66 g, 43.8 mmol) under nitrogen protection. After the addition was complete, the reaction was stirred overnight at room temperature. The reaction was then quenched with a minimum amount of saturated sodium sulfate aqueous solution at a freezing temperature. The slurry mixture was filtered under vacuum and the residue was washed with ethyl acetate. The combined filtrate was dried over anhydrous sodium sulfate and then the solvent was dried to give a white solid product (4.6 g, 10 mmol) with a yield of 92%. 1 HNMR (400MHz, DMSO-d6) δ7.22-7.41(m,5H),5.48(d,2H),4.61-4.90(m,6H),4.50(t,1H),3.20-3.98(m,13H),3.02-3.17(dd,2H),1.60(s,2H).

[0057] Example 2 (Compound 1)

[0058] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-phenylethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0059] Add the amine of Example 1 (4.6 g, 10 mmol) and 50 mL of ethanol to the reaction flask, then add 1-(1,3-benzodioxol-5-yl)-2-propanone (1.96 g, 11 mmol), and finally drop 1 mL of glacial acetic acid. After the addition is complete, stir at room temperature for 2 h. Next, add 0.2 g (10%) of Raney nickel, pass H2, 50 psi into a high-pressure reactor, and react at room temperature overnight. Filter off the solid (the solid waste is stored in water), add concentrated hydrochloric acid to the filtrate to adjust the pH to 1, and stir for 1 h. Spin dry the solvent, add ethanol / THF to slurry, freeze in the refrigerator, and filter to obtain the product hydrochloride (3.8 g, 5.8 mmol) with a yield of 58%. 1H NMR(400MHz,DMSO-d6)δ7.28-7.40(m,5H),6.75-6.82(m,3H),5.98(s,2H),5.52(s,1H),5.40(d,2H),4 .71-4.88(m,6H),4.53(t,1H),3.20-3.98(m,13H),2.92-3.10(m,3H),2.51-2.72(dd,2H),1.11(d,3H).

[0060] Example 3 2-Hydroxy-2-(pyridin-3-yl)acetonitrile

[0061] Under 0℃, 3-pyridinecarboxaldehyde (3.0 g, 28.0 mmol) and acetic acid (1.68 g, 28.0 mmol) aqueous solution were added to TMSCN (3.7 g, 37.2 mmol) aqueous solution. The reaction was carried out at room temperature for 23 hours and extracted with AcOEt (3×20 mL). The organic phases were combined, dried over anhydrous Na2SO4, and then the solvent was dried to obtain the desired product as an orange-yellow oil (3.36 g, 25.1 mmol) with a yield of 89%. 1 H NMR (400MHz, CDCl3) δ 8.62 (d, J = 2.0 Hz, 1H), 8.53 (d, J = 4.7 Hz, 1H), 7.96 (dt, J = 7.9, 1.6 Hz), 7.42 (dd, J = 7.9, 5.0 Hz), 5.65 (s, 1H).

[0062] Example 4

[0063] (2R,3R,4S,5S,6R)-2-(2-amino-1-(pyridin-3-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0064] Gentiobiose (11.7 g, 34.2 mmol), nitrile (3.36 g, 25.1 mmol) in Example 3 and 100 mL of methanol were added to the reaction flask, stirred and heated to 50 ° C. Under nitrogen protection, acetyl chloride (6 mL, 0.084 mmol) was slowly added to the solution. The resulting mixture was stirred at 50 ° C for 2 h, then the heating device was removed and continued to stir at room temperature for 15 h. The reaction mixture was poured into water (100 mL) and washed with EtOAc (3 x 25 mL). The combined organic phase was washed with water (2 x 50 mL), and the combined aqueous phase was concentrated under reduced pressure to obtain a transparent oily residue, which was recrystallized in EtOAc / Hex to obtain a white crystalline solid product (2.6 g, 5.7 mmol). It was then dissolved in 10 mL of tetrahydrofuran and slowly added dropwise to a stirred suspension of tetrahydrofuran / LiAlH4 (0.86 g, 22.8 mmol) under nitrogen protection. After the drop was completed, the reaction was stirred at room temperature overnight. The reaction was then quenched with a minimum amount of saturated sodium sulfate aqueous solution at freezing temperature. The slurry mixture was filtered under vacuum and the residue was washed with ethyl acetate. The combined filtrate was dried over anhydrous sodium sulfate and the solvent was then dried to give a white solid product (1.9 g, 4.1 mmol) with a two-step yield of 16%. 1 HNMR(400MHz,DMSO-d6)δ8.54(s,1H),8.38(d,1H),7.86(d,1H)7.38(t,1H),5.40(d,2H ),4.63-4.88(m,6H),4.54(t,1H),3.22-3.95(m,13H),3.06-3.14(dd,2H),1.61(s,2H).

[0065] Example 5 (Compound 2)

[0066] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(pyridin-3-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0067] Following the same procedure as in Example 2, starting from the amine described in Example 4 (1.9 g, 4.1 mmol), the title compound (1.4 g, 2.2 mmol) was obtained in a yield of 54%. 1H NMR(400MHz,DMSO-d6)δ8.52(s,1H),8.34(d,1H),7.84(d,1H)7.33(t,1H),6.74-6.83(m,3H),5.96(s,2H),5.51(s,1H) ,5.44(d,2H),4.74-4.84(m,6H),4.58(t,1H),3.21-3.98(m,13H),2.94-3.14(m,3H),2.50-2.71(dd,2H),1.15(d,3H).

[0068] Example 6 2-Hydroxy-2-(pyridin-4-yl)acetonitrile

[0069] Following the same method as in Example 3, starting from isonicotinaldehyde (3.0 g, 28.0 mmol), the title compound (1.49 g, 11.2 mmol) was obtained with a yield of 40%. 1 HNMR (400MHz, CDCl3) δ8.61(d,2H),7.46(d,2H),5.88(s,1H).

[0070] Example 7

[0071] (2R,3R,4S,5S,6R)-2-(2-amino-1-(pyridin-4-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0072] Following the same procedure as in Example 4, starting from the nitrile described in Example 7 (1.49 g, 11.2 mmol), the title compound (1.11 g, 2.4 mmol) was obtained in a yield of 21%. 1 H NMR(400MHz,DMSO-d6)δ8.60(d,2H),7.45(d,2H),5.42(d,2H),4.61-4.86 (m,6H),4.55(t,1H),3.20-3.91(m,13H),3.02-3.12(dd,2H),1.60(s,2H).

[0073] Example 8 (Compound 3)

[0074] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(pyridin-4-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0075] Following the same procedure as in Example 2, starting from the amine described in Example 7 (1.11 g, 2.4 mmol), the title compound (0.93 g, 1.5 mmol) was obtained in a yield of 62%. 1 H NMR(400MHz,DMSO-d6)δ8.58(d,2H),7.42(d,2H),6.72-6.83(m,3H),5.92(s,2H),5.56(s,1H),5.42(d,2H ),4.72-4.84(m,6H),4.51(t,1H),3.25-3.91(m,13H),2.90-3.12(m,3H),2.51-2.70(dd,2H),1.14(d,3H).

[0076] Example 9 2-Hydroxy-2-(p-tolyl)acetonitrile

[0077] Following the same method as in Example 3, starting from p-methylbenzaldehyde (3.0 g, 25.0 mmol), the title compound (3.33 g, 22.7 mmol) was obtained with a yield of 91%. 1 H NMR (400MHz, CDCl3) δ7.23(d,2H),7.09(d,2H),5.88(s,1H),2.19(s,3H).

[0078] Example 10

[0079] (2R,3R,4S,5S,6R)-2-(2-amino-1-(p-tolyl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0080] Following the same procedure as in Example 4, starting from the nitrile described in Example 9 (3.33 g, 22.7 mmol), the title compound (3.47 g, 7.3 mmol) was obtained in a yield of 32%. 1H NMR(400MHz,DMSO-d6)δ7.21(d,2H),7.11(d,2H),5.44(d,2H),4.68-4.88(m,6H) ,4.65(t,1H),3.25-3.82(m,13H),3.00-3.10(dd,2H),2.14(s,3H),1.62(s,2H).

[0081] Example 11 (Compound 4)

[0082] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(p-tolyl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0083] Following the same procedure as in Example 2, starting from the amine described in Example 11 (3.47 g, 7.3 mmol), the title compound (3.21 g, 5.0 mmol) was obtained in a yield of 69%. 1 H NMR(400MHz,DMSO-d6)δ7.24(d,2H),7.10(d,2H),6.71-6.73(m,3H),5.95(s,2H),5.52(s,1H),5.42(d,2H),4.73 -4.86(m,6H),4.54(t,1H),3.23-3.94(m,13H),2.91-3.14(m,3H),2.52-2.71(dd,2H),2.16(s,3H),1.15(d,3H).

[0084] Example 12 2-(4-Fluorophenyl)-2-hydroxyacetonitrile

[0085] Following the same procedure as in Example 3, starting from p-fluorobenzaldehyde (3.0 g, 24.2 mmol), the title compound (3.21 g, 21.3 mmol) was obtained with a yield of 88%. 1 H NMR (400MHz, CDCl3) δ7.26(d,2H),7.19(d,2H),5.89(s,1H).

[0086] Embodiment 13

[0087] (2R,3R,4S,5S,6R)-2-(2-amino-1-(4-fluorophenyl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0088] Following the same procedure as in Example 4, starting from the nitrile described in Example 12 (3.21 g, 21.3 mmol), the title compound (2.65 g, 5.5 mmol) was obtained in a yield of 26%. 1 H NMR(400MHz,DMSO-d6)δ7.28(d,2H),7.22(d,2H),5.45(d,2H),4.65-4.89 (m,6H),4.85(t,1H),3.35-3.92(m,13H),3.10-3.19(dd,2H),1.68(s,2H).

[0089] Example 14 (Compound 5)

[0090] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(4-fluorophenyl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0091] Following the same procedure as in Example 2, starting from the amine described in Example 13 (2.65 g, 5.5 mmol), the title compound (2.51 g, 3.9 mmol) was obtained in a yield of 71%. 1 H NMR(400MHz,DMSO-d6)δ7.27(d,2H),7.24(d,2H),6.74-6.76(m,3H),5.94(s,2H),5.54(s,1H),5.46(d,2H ),4.74-4.86(m,6H),4.55(t,1H),3.21-3.93(m,13H),2.90-3.12(m,3H),2.50-2.70(dd,2H),1.16(d,3H).

[0092] Example 15 2-(4-Chlorophenyl)-2-hydroxyacetonitrile

[0093] Following the same procedure as in Example 3, starting from p-chlorobenzaldehyde (3.0 g, 21.4 mmol), the title compound (2.93 g, 17.5 mmol) was obtained with a yield of 82%. 1 H NMR (400MHz, CDCl3) δ7.24(d,2H),7.15(d,2H),5.88(s,1H).

[0094] Example 16

[0095] (2R,3R,4S,5S,6R)-2-(2-amino-1-(4-chlorophenyl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0096] Following the same procedure as in Example 4, starting from the nitrile described in Example 15 (2.93 g, 17.5 mmol), the title compound (1.82 g, 3.7 mmol) was obtained in a yield of 21%. 1 H NMR(400MHz,DMSO-d6)δ7.25(d,2H),7.20(d,2H),5.41(d,2H),4.64-4.85 (m,6H),4.81(t,1H),3.32-3.88(m,13H),3.03-3.18(dd,2H),1.67(s,2H).

[0097] Example 17 (Compound 6)

[0098] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(4-chlorophenyl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0099] Following the same procedure as in Example 2, starting from the amine described in Example 16 (1.82 g, 3.7 mmol), the title compound (1.61 g, 2.4 mmol) was obtained in a yield of 66%. 1H NMR(400MHz,DMSO-d6)δ7.24(d,2H),7.21(d,2H),6.71-6.75(m,3H),5.94(s,2H),5.55(s,1H),5.41(d,2H ),4.72-4.84(m,6H),4.54(t,1H),3.22-3.95(m,13H),2.91-3.14(m,3H),2.52-2.71(dd,2H),1.14(d,3H).

[0100] Example 18 2-(4-bromophenyl)-2-hydroxyacetonitrile

[0101] Following the same method as in Example 3, starting from p-bromobenzaldehyde (3.0 g, 16.2 mmol), the title compound (2.92 g, 13.8 mmol) was obtained with a yield of 85%. 1 H NMR (400MHz, CDCl3) δ7.22(d,2H),7.13(d,2H),5.87(s,1H).

[0102] Embodiment 19

[0103] (2R,3R,4S,5S,6R)-2-(2-amino-1-(4-bromophenyl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0104] Following the same procedure as in Example 4, starting from the nitrile described in Example 18 (2.92 g, 13.8 mmol), the title compound (1.34 g, 2.5 mmol) was obtained in a yield of 18%. 1 H NMR(400MHz,DMSO-d6)δ7.23(d,2H),7.19(d,2H),5.40(d,2H),4.61-4.82 (m,6H),4.80(t,1H),3.31-3.82(m,13H),3.01-3.16(dd,2H),1.66(s,2H).

[0105] Example 20 (Compound 7)

[0106] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(4-bromophenyl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0107] Following the same procedure as in Example 2, starting from the amine described in Example 19 (1.34 g, 2.5 mmol), the title compound (1.09 g, 1.6 mmol) was obtained in a yield of 62%. 1 H NMR(400MHz,DMSO-d6)δ7.20(d,2H),7.18(d,2H),6.70-6.75(m,3H),5.93(s,2H),5.54(s,1H),5.42(d,2H ),4.70-4.81(m,6H),4.52(t,1H),3.21-3.93(m,13H),2.92-3.11(m,3H),2.53-2.73(dd,2H),1.16(d,3H).

[0108] Example 21 2-Hydroxy-2-(4-methoxyphenyl)acetonitrile

[0109] Following the same method as in Example 3, starting from p-anisaldehyde (3.0 g, 22.1 mmol), the title compound (2.95 g, 18.1 mmol) was obtained with a yield of 82%. 1 H NMR (400MHz, CDCl3) δ7.28(d,2H),6.89(d,2H),5.88(s,1H),3.81(s,3H).

[0110] Embodiment 22

[0111] (2R,3R,4S,5S,6R)-2-(2-amino-1-(4-methoxyphenyl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0112] Following the same procedure as in Example 4, starting from the nitrile described in Example 21 (2.95 g, 18.1 mmol), the title compound (2.31 g, 4.7 mmol) was obtained in a yield of 26%. 1H NMR(400MHz,DMSO-d6)δ7.29(d,2H),6.88(d,2H),5.45(d,2H),4.64-4.85(m,6H) ,4.66(t,1H),3.24-3.81(m,13H),3.01-3.12(dd,2H),3.83(s,3H),1.64(s,2H).

[0113] Example 23 (Compound 8)

[0114] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(4-methoxyphenyl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0115] Following the same procedure as in Example 2, starting from the amine described in Example 22 (2.31 g, 4.7 mmol), the title compound (1.97 g, 3.0 mmol) was obtained in a yield of 64%. 1 H NMR(400MHz,DMSO-d6)δ7.28(d,2H),6.87(d,2H),6.70-6.72(m,3H),5.93(s,2H),5.42(s,1H),5.39(d,2H),4.70 -4.85(m,6H),4.52(t,1H),3.21-3.91(m,13H),2.92-3.16(m,3H),2.52-2.72(dd,2H),3.84(s,3H),1.17(d,3H).

[0116] Example 24 2-(4-Aminophenyl)-2-hydroxyacetonitrile

[0117] Following the same procedure as in Example 3, starting from p-aminobenzaldehyde (3.0 g, 24.8 mmol), the title compound (3.16 g, 21.3 mmol) was obtained with a yield of 86%. 1 H NMR (400MHz, CDCl3) δ7.13(d,2H),6.48(d,2H),5.88(s,1H).

[0118] Embodiment 25

[0119] (2R,3R,4S,5S,6R)-2-(2-amino-1-(p-aminophenyl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0120] The same method as in Example 4 was used to prepare the nitrile described in Example 24 (3.16 g, 21.3 mmol), except that the amino group needed to be Boc-protected first, and dichloromethane was used as solvent at room temperature, Boc2O was added, and finally deprotected in dilute hydrochloric acid to obtain the title compound (1.93 g, 4.0 mmol) with a yield of 19%. 1 H NMR(400MHz,DMSO-d6)δ7.13(d,2H),6.48(d,2H),5.40(d,2H),4.91(d,2H),4.66 -4.86(m,6H),4.64(t,1H),3.24-3.81(m,13H),3.01-3.10(dd,2H),1.60(s,2H).

[0121] Example 26 (Compound 9)

[0122] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(p-aminophenyl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0123] Following the same procedure as in Example 2, starting from the amine described in Example 25 (1.93 g, 4.0 mmol), the title compound (1.56 g, 2.4 mmol) was obtained in a yield of 61%. 1 H NMR(400MHz,DMSO-d6)δ7.12(d,2H),6.49(d,2H),6.70-6.72(m,3H),5.96(s,2H),5.54(s,1H),5.44(d,2H),4.90 (d,2H),4.71-4.83(m,6H),4.52(t,1H),3.21-3.93(m,13H),2.92-3.16(m,3H),2.50-2.70(dd,2H),1.16(d,3H).

[0124] Example 27 2-Hydroxy-2-(4-nitrophenyl)acetonitrile

[0125] Following the same method as in Example 3, starting from p-nitrobenzaldehyde (3.0 g, 19.9 mmol), the title compound (1.98 g, 11.1 mmol) was obtained with a yield of 56%. 1 H NMR (400MHz, CDCl3) δ8.20(d,2H),7.54(d,2H),5.87(s,1H).

[0126] Embodiment 28

[0127] (2R,3R,4S,5S,6R)-2-(2-amino-1-(4-nitrophenyl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0128] Following the same procedure as in Example 4, starting from the nitrile described in Example 27 (1.98 g, 11.1 mmol), the title compound (1.29 g, 2.6 mmol) was obtained in a yield of 23%. 1 H NMR(400MHz,DMSO-d6)δ8.22(d,2H),7.56(d,2H),5.43(d,2H),4.62-4.88 (m,6H),4.56(t,1H),3.21-3.91(m,13H),3.00-3.14(dd,2H),1.61(s,2H).

[0129] Example 29 (Compound 10)

[0130] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(4-nitrophenyl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0131] Following the same procedure as in Example 2, starting from the amine described in Example 28 (1.29 g, 2.6 mmol), the title compound (1.18 g, 1.8 mmol) was obtained in a yield of 68%. 1H NMR(400MHz,DMSO-d6)δ8.20(d,2H),7.55(d,2H),6.76-6.84(m,3H),5.95(s,2H),5.55(s,1H),5.46(d,2H ),4.73-4.84(m,6H),4.53(t,1H),3.25-3.90(m,13H),2.91-3.12(m,3H),2.52-2.72(dd,2H),1.15(d,3H).

[0132] Example 30 2-Hydroxy-2-(4-cyanophenyl)acetonitrile

[0133] Following the same method as in Example 3, starting from 4-formylbenzonitrile (3.0 g, 22.9 mmol), the title compound (1.74 g, 11.0 mmol) was obtained with a yield of 48%. 1 H NMR (400MHz, CDCl3) δ7.76(d,2H),7.46(d,2H),5.89(s,1H).

[0134] Embodiment 31

[0135] 4-(2-Amino-1-(((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)ethyl)benzonitrile

[0136] Following the same procedure as in Example 4, starting from the nitrile described in Example 30 (1.74 g, 11.0 mmol), the title compound (1.22 g, 2.3 mmol) was obtained in a yield of 21%. 1 H NMR(400MHz,DMSO-d6)δ7.74(d,2H),7.45(d,2H),5.42(d,2H),4.60-4.88 (m,6H),4.54(t,1H),3.19-3.91(m,13H),3.04-3.14(dd,2H),1.60(s,2H).

[0137] Example 32 (Compound 11)

[0138] 4-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)ethyl)benzonitrile

[0139] Following the same procedure as in Example 2, starting from the amine described in Example 31 (1.22 g, 2.3 mmol), the title compound (0.78 g, 1.2 mmol) was obtained in a yield of 52%. 1 H NMR(400MHz,DMSO-d6)δ7.73(d,2H),7.51(d,2H),6.75-6.79(m,3H),5.96(s,2H),5.54(s,1H),5.44(d,2H ),4.73-4.85(m,6H),4.54(t,1H),3.26-3.90(m,13H),2.91-3.15(m,3H),2.54-2.73(dd,2H),1.16(d,3H).

[0140] Example 33 2-Hydroxy-2-(4-trifluoromethylphenyl)acetonitrile

[0141] Following the same procedure as in Example 3, starting from 4-trifluoromethylbenzaldehyde (3.0 g, 17.2 mmol), the title compound (1.94 g, 9.7 mmol) was obtained with a yield of 56%. 1 H NMR (400MHz, CDCl3) δ7.54(d,2H),7.21(d,2H),5.88(s,1H).

[0142] Embodiment 34

[0143] (2R,3R,4S,5S,6R)-2-(2-amino-1-(4-(trifluoromethyl)phenyl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0144] Following the same procedure as in Example 4, starting from the nitrile described in Example 33 (1.94 g, 9.7 mmol), the title compound (1.38 g, 2.6 mmol) was obtained in a yield of 27%. 1H NMR(400MHz,DMSO-d6)δ7.52(d,2H),7.22(d,2H),5.41(d,2H),4.61-4.88 (m,6H),4.53(t,1H),3.18-3.91(m,13H),3.06-3.14(dd,2H),1.61(s,2H).

[0145] Example 35 (Compound 12)

[0146] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(4-(trifluoromethyl)phenyl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0147] Following the same procedure as in Example 2, starting from the amine described in Example 34 (1.38 g, 2.6 mmol), the title compound (0.83 g, 1.2 mmol) was obtained in a yield of 46%. 1 H NMR(400MHz,DMSO-d6)δ7.53(d,2H),7.21(d,2H),6.74-6.78(m,3H),5.93(s,2H),5.52(s,1H),5.38(d,2H ),4.73-4.84(m,6H),4.53(t,1H),3.26-3.91(m,13H),2.91-3.20(m,3H),2.54-2.83(dd,2H),1.14(d,3H).

[0148] Example 36 2-(Benzo[d][1,3]dioxol-5-yl)-2-hydroxyacetonitrile

[0149] Following the same procedure as in Example 3, starting from benzo[d][1,3]dioxole-5-carbaldehyde (3.0 g, 20 mmol), the title compound (1.70 g, 9.6 mmol) was obtained with a yield of 48%. 1 H NMR (400MHz, CDCl3) δ6.97(d,2H),6.87(d,2H),5.97(s,2H),5.88(s,1H).

[0150] Embodiment 37

[0151] (2R,3R,4S,5S,6R)-2-(2-amino-1-(benzo[d][1,3]dioxol-5-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0152] Following the same procedure as in Example 4, starting from the nitrile described in Example 36 (1.70 g, 9.6 mmol), the title compound (1.60 g, 3.2 mmol) was obtained in a yield of 33%. 1 H NMR(400MHz,DMSO-d6)δ6.97(s,1H),6.96(d,1H),6.87(d,1H),5.97(s,2H),5.40(d,2H ),4.58-4.78(m,6H),4.54(t,1H),3.18-3.92(m,13H),3.06-3.16(dd,2H),1.60(s,2H).

[0153] Example 38 (Compound 13)

[0154] (2R,3R,4S,5S,6R)-2-((1R)-1-(Benzo[d][1,3]dioxol-5-yl)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0155] Following the same procedure as in Example 2, starting from the amine described in Example 37 (1.60 g, 3.2 mmol), the title compound (0.94 g, 1.4 mmol) was obtained in a yield of 44%. 1 H NMR(400MHz,DMSO-d6)δ6.74-6.97(m,6H),5.97(s,2H),5.93(s,2H),5.53(s,1H),5.40(d,2H),4.72 -4.84(m,6H),4.51(t,1H),3.26-3.93(m,13H),2.91-3.22(m,3H),2.54-2.73(dd,2H),1.16(d,3H).

[0156] Example 39 2-(2,3-dihydrobenzofuran-6-yl)-2-hydroxyacetonitrile

[0157] Following the same procedure as in Example 3, starting from 2,3-dihydrobenzofuran-6-carbaldehyde (3.0 g, 20.3 mmol), the title compound (1.81 g, 10.3 mmol) was obtained with a yield of 51%. 1 HNMR (400MHz, CDCl3) δ7.23(s,1H),7.18(d,1H),6.79(d,1H),5.88(s,1H),4.27(t,2H),2.97(t,2H).

[0158] Embodiment 40

[0159] (2R,3R,4S,5S,6R)-2-(2-amino-1-(2,3-dihydrobenzofuran-6-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0160] Following the same procedure as in Example 4, starting from the nitrile described in Example 39 (1.81 g, 10.3 mmol), the title compound (1.35 g, 2.7 mmol) was obtained in a yield of 26%. 1 H NMR(400MHz,DMSO-d6)δ7.22(s,1H),7.19(d,1H),6.78(d,1H),5.41(d,2H),4.58-4.76(m,6H) ,4.52(t,1H),4.28(t,2H),3.18-3.82(m,13H),3.06-3.23(dd,2H),2.95(t,2H),1.60(s,2H).

[0161] Example 41 (Compound 14)

[0162] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(2,3-dihydrobenzofuran-6-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0163] Following the same procedure as in Example 2, starting from the amine described in Example 40 (1.35 g, 2.7 mmol), the title compound (0.59 g, 0.89 mmol) was obtained in a yield of 33%. 1H NMR(400MHz,DMSO-d6)δ6.74-7.22(m,6H),5.93(s,2H),5.53(s,1H),5.40(d,2H),4.72-4.84(m,6H) ,4.51(t,1H),4.27(t,2H),3.26-3.93(m,13H),2.91-3.22(m,5H),2.54-2.73(dd,2H),1.16(d,3H).

[0164] Example 42 2-Hydroxy-2-(1H-indol-6-yl)acetonitrile

[0165] Following the same procedure as in Example 3, starting from 1H-indole-5-carboxaldehyde (3.0 g, 20.7 mmol), the title compound (2.17 g, 12.6 mmol) was obtained with a yield of 61%. 1 H NMR (400MHz, CDCl3) δ10.1(s,1H),8.15(s,1H),7.61(d,1H),7.55(d,1H),7.07(d,1H),6.56(d,1H),5.88(s,1H).

[0166] Embodiment 43

[0167] (2R,3R,4S,5S,6R)-2-(2-amino-1-(1H-indol-6-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0168] Following the same procedure as in Example 4, starting from the nitrile described in Example 42 (2.17 g, 12.6 mmol), the title compound (1.95 g, 3.9 mmol) was obtained in a yield of 31%. 1 H NMR(400MHz,DMSO-d6)δ10.1(s,1H),8.14(s,1H),7.63(d,1H),7.54(d,1H),7.05(d,1H),6.54(d,1H ),5.40(d,2H),4.58-4.66(m,6H),4.54(t,1H),3.18-3.83(m,13H),3.06-3.25(dd,2H),1.61(s,2H).

[0169] Example 44 (Compound 15)

[0170] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(1H-indol-6-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0171] Following the same procedure as in Example 2, starting from the amine described in Example 43 (1.95 g, 3.9 mmol), the title compound (1.06 g, 1.60 mmol) was obtained in a yield of 41%. 1 H NMR(400MHz,DMSO-d6)δ10.1(s,1H),8.14(s,1H),7.63(d,1H),7.54(d,1H),6.74-7.22(m,4H),6.54(d,1H),5.93(s,2H),5.53 (s,1H),5.40(d,2H),4.72-4.84(m,6H),4.51(t,1H),3.26-3.93(m,13H),2.91-3.22(m,3H),2.54-2.73(dd,2H),1.16(d,3H).

[0172] Example 45 2-Hydroxy-2-(1H-indazol-6-yl)acetonitrile

[0173] Following the same procedure as in Example 3, starting from 1H-indazole-6-carbaldehyde (3.0 g, 20.5 mmol), the title compound (1.96 g, 11.3 mmol) was obtained with a yield of 55%. 1 H NMR (400MHz, CDCl3) δ12.4(s,1H),8.35(d,1H),8.20(s,1H),7.85(s,1H),7.34(d,1H),5.88(s,1H).

[0174] Embodiment 46

[0175] (2R,3R,4S,5S,6R)-2-(2-amino-1-(1H-indazol-6-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0176] Following the same procedure as in Example 4, starting from the nitrile described in Example 45 (1.96 g, 11.3 mmol), the title compound (2.26 g, 4.5 mmol) was obtained in a yield of 40%. 1 H NMR(400MHz,DMSO-d6)δ12.1(s,1H),8.33(d,1H),8.19(s,1H),7.75(s,1H),7.36(d,1H),5.41 (d,2H),4.58-4.62(m,6H),4.55(t,1H),3.19-3.83(m,13H),3.08-3.25(dd,2H),1.60(s,2H).

[0177] Example 47 (Compound 16)

[0178] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(1H-indazol-6-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0179] Following the same procedure as in Example 2, starting from the amine described in Example 46 (2.26 g, 4.5 mmol), the title compound (0.87 g, 1.3 mmol) was obtained in a yield of 29%. 1 H NMR(400MHz,DMSO-d6)δ12.0(s,1H),8.31(d,1H),8.14(s,1H),7.77(s,1H),7.46(d,1H),6.72-7.22(m,3H),6.54(d,1H),5.93(s,2H ),5.53(s,1H),5.40(d,2H),4.70-4.84(m,6H),4.53(t,1H),3.26-3.93(m,13H),2.91-3.25(m,3H),2.54-2.76(dd,2H),1.13(d,3H).

[0180] Example 48 2-(1H-Benzo[d][1,2,3]triazol-6-yl)-2-hydroxyacetonitrile

[0181] Following the same procedure as in Example 3, starting from 1H-benzo[d][1,2,3]triazole-6-carbaldehyde (3.0 g, 20.4 mmol), the title compound (1.74 g, 10 mmol) was obtained in a yield of 49%. 1HNMR (400MHz, CDCl3) δ16.1(s,1H),8.24(s,1H),7.92(d,1H),7.85(d,1H),5.88(s,1H).

[0182] Embodiment 49

[0183] (2R,3R,4S,5S,6R)-2-(2-amino-1-(1H-benzo[d][1,2,3]triazol-6-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0184] Following the same procedure as in Example 4, starting from the nitrile described in Example 48 (1.74 g, 10 mmol), the title compound (1.61 g, 3.2 mmol) was obtained in a yield of 32%. 1 H NMR(400MHz,DMSO-d6)δ16.2(s,1H),8.22(s,1H),7.96(d,1H),7.86(d,1H),5.40(d,2H ),4.55-4.63(m,6H),4.56(t,1H),3.19-3.84(m,13H),3.08-3.24(dd,2H),1.61(s,2H).

[0185] Example 50 (Compound 17)

[0186] (2R,3R,4S,5S,6R)-2-((1R)-1-(1H-benzo[d][1,2,3]triazol-6-yl)-2-((1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0187] Following the same procedure as in Example 2, starting from the amine described in Example 49 (1.61 g, 3.2 mmol), the title compound (0.77 g, 1.2 mmol) was obtained in a yield of 36%. 1H NMR(400MHz,DMSO-d6)δ16.0(s,1H),8.21(s,1H),7.95(d,1H),7.84(d,1H),6.73-7.24(m,3H),6.55(d,1H),5.92(s,2H),5.53 (s,1H),5.42(d,2H),4.71-4.84(m,6H),4.52(t,1H),3.26-3.93(m,13H),2.91-3.26(m,3H),2.54-2.74(dd,2H),1.14(d,3H).

[0188] Example 51 2-(1H-Benzo[d]imidazol-6-yl)-2-hydroxyacetonitrile

[0189] Following the same procedure as in Example 3, starting from 1H-benzo[d]imidazole-6-carbaldehyde (3.0 g, 20.5 mmol), the title compound (1.35 g, 7.8 mmol) was obtained in a yield of 38%. 1 H NMR (400MHz, CDCl3) δ12.4(s,1H),8.19(s,1H),7.66(d,1H),7.52(s,1H),7.20(d,1H),5.88(s,1H).

[0190] Embodiment 52

[0191] (2R,3R,4S,5S,6R)-2-(2-amino-1-(1H-benzo[d]imidazol-6-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0192] Following the same procedure as in Example 4, starting from the nitrile described in Example 51 (1.35 g, 7.8 mmol), the title compound (1.17 g, 2.3 mmol) was obtained in a yield of 30%. 1 H NMR(400MHz,DMSO-d6)δ12.2(s,1H),8.14(s,1H),7.60(d,1H),7.56(s,1H),7.21(d,1H),5.42 (d,2H),4.55-4.65(m,6H),4.53(t,1H),3.19-3.82(m,13H),3.08-3.25(dd,2H),1.63(s,2H).

[0193] Example 53 (Compound 18)

[0194] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(1H-benzo[d]imidazol-6-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0195] Following the same procedure as in Example 2, starting from the amine described in Example 52 (1.17 g, 2.3 mmol), the title compound (0.66 g, 1.0 mmol) was obtained in a yield of 43%. 1 H NMR(400MHz,DMSO-d6)δ12.0(s,1H),8.11(s,1H),7.65(d,1H),7.54(s,1H),6.73-7.24(m,4H),6.53(d,1H),5.90(s,2H),5.50 (s,1H),5.42(d,2H),4.71-4.82(m,6H),4.52(t,1H),3.24-3.93(m,13H),2.91-3.26(m,3H),2.52-2.74(dd,2H),1.12(d,3H).

[0196] Example 54 2-Hydroxy-2-(1,2,3,4-tetrahydroquinolin-6-yl)acetonitrile

[0197] Following the same procedure as in Example 3, starting from 1,2,3,4-tetrahydroquinoline-6-carbaldehyde (3.0 g, 18.6 mmol), the title compound (0.81 g, 4.3 mmol) was obtained with a yield of 23%. 1 H NMR (400MHz, CDCl3) δ7.13(s,1H),7.08(d,1H),6.70(d,1H),5.88(s,1H),3.04(t,2H),2.79(t,2H),1.96(m,2H).

[0198] Embodiment 55

[0199] (2R,3R,4S,5S,6R)-2-(2-amino-1-(1,2,3,4-tetrahydroquinolin-6-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0200] The same method as in Example 4 was used to prepare the nitrile described in Example 54 (0.81 g, 4.3 mmol), except that the secondary amine needed to be Boc-protected first, and dichloromethane was used as solvent at room temperature, Boc2O was added, and finally deprotection was performed under dilute hydrochloric acid conditions to obtain the title compound (0.84 g, 1.6 mmol) with a yield of 38%. 1 H NMR(400MHz,DMSO-d6)δ7.15(s,1H),7.06(d,1H),6.75(d,1H),5.43(d,2H),4.58-4.65(m,6H),4.55 (t,1H),3.20-3.80(m,13H),3.09-3.25(dd,2H),3.01(t,2H),2.77(t,2H),1.94(m,2H),1.60(s,2H).

[0201] Example 56 (Compound 19)

[0202] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(1,2,3,4-tetrahydroquinolin-6-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0203] Following the same procedure as in Example 2, starting from the amine described in Example 55 (0.84 g, 1.6 mmol), the title compound (0.14 g, 0.2 mmol) was obtained in a yield of 13%. 1 H NMR(400MHz,DMSO-d6)δ6.70-7.24(m,6H),6.53(d,1H),5.90(s,2H),5.50(s,1H),5.42(d,2H),4.71-4.82(m,6H) ,4.52(t,1H),3.24-3.93(m,13H),2.91-3.26(m,5H),2.79(t,2H),2.52-2.74(dd,2H),1.96(m,2H),1.12(d,3H).

[0204] Example 57 2-Hydroxy-2-(naphthalen-2-yl)acetonitrile

[0205] Following the same method as in Example 3, starting from 2-naphthaldehyde (3.0 g, 19.2 mmol), the title compound (1.55 g, 8.5 mmol) was obtained with a yield of 44%. 1H NMR (400MHz, CDCl3) δ7.90-8.01(m,3H),7.71(s,1H),7.48-7.58(m,3H),5.88(s,1H).

[0206] Embodiment 58

[0207] (2R,3R,4S,5S,6R)-2-(2-amino-1-(naphthalen-2-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0208] Following the same procedure as in Example 4, starting from the nitrile described in Example 57 (1.55 g, 8.5 mmol), the title compound (2.39 g, 4.7 mmol) was obtained in a yield of 55%. 1 H NMR(400MHz,DMSO-d6)δ7.90-8.03(m,3H),7.72(s,1H),7.48-7.57(m,3H),5.43(d,2H) ,4.55-4.67(m,6H),4.54(t,1H),3.19-3.81(m,13H),3.08-3.15(dd,2H),1.61(s,2H).

[0209] Example 59 (Compound 20)

[0210] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(naphthalen-2-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0211] Following the same procedure as in Example 2, starting from the amine described in Example 58 (2.39 g, 4.7 mmol), the title compound (1.20 g, 1.8 mmol) was obtained in a yield of 38%. 1H NMR(400MHz,DMSO-d6)δ7.90-8.03(m,3H),7.73(s,1H),7.48-7.61(m,3H),6.73-7.26(m,3H),6.51(d,1H),5.90(s,2H),5.51 (s,1H),5.42(d,2H),4.71-4.82(m,6H),4.56(t,1H),3.22-3.90(m,13H),2.91-3.26(m,3H),2.52-2.73(dd,2H),1.13(d,3H).

[0212] Example 60 2-Hydroxy-2-(quinolin-6-yl)acetonitrile

[0213] Following the same method as in Example 3, starting from quinoline-6-carboxaldehyde (3.0 g, 19.1 mmol), the title compound (1.27 g, 6.9 mmol) was obtained with a yield of 36%. 1 H NMR (400MHz, CDCl3) δ8.85(d,1H),7.95-8.05(m,3H),7.70(d,1H),7.35(t,1H),5.88(s,1H).

[0214] Embodiment 61

[0215] (2R,3R,4S,5S,6R)-2-(2-amino-1-(quinolin-6-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0216] Following the same procedure as in Example 4, starting from the nitrile described in Example 60 (1.27 g, 6.9 mmol), the title compound (1.63 g, 3.2 mmol) was obtained in a yield of 46%. 1 H NMR(400MHz,DMSO-d6)δ8.85(d,1H),7.95-8.05(m,3H),7.71(d,1H),7.36(t,1H),5.43(d, 2H),4.55-4.67(m,6H),4.54(t,1H),3.19-3.81(m,13H),3.08-3.16(dd,2H),1.63(s,2H).

[0217] Example 62 (Compound 21)

[0218] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(quinolin-6-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0219] Following the same procedure as in Example 2, starting from the amine described in Example 61 (1.63 g, 3.2 mmol), the title compound (0.88 g, 1.3 mmol) was obtained in a yield of 41%. 1 H NMR(400MHz,DMSO-d6)δ8.85(d,1H),7.96-8.04(m,3H),7.70(d,1H),7.38(t,1H),6.73-7.24(m,3H),6.51(d,1H),5.90(s,2H),5 .51(s,1H),5.40(d,2H),4.71-4.86(m,6H),4.58(t,1H),3.22-3.90(m,13H),2.91-3.20(m,3H),2.52-2.71(dd,2H),1.13(d,3H).

[0220] Example 63 2-Hydroxy-2-(naphthalen-1-yl)acetonitrile

[0221] Following the same method as in Example 3, starting from 1-naphthaldehyde (3.0 g, 19.2 mmol), the title compound (1.44 g, 7.9 mmol) was obtained with a yield of 41%. 1 H NMR (400MHz, CDCl3) δ8.01-8.05(m,3H),7.51-7.62(m,2H),7.43(m,1H),7.06(d,1H),5.88(s,1H).

[0222] Embodiment 64

[0223] (2R,3R,4S,5S,6R)-2-(2-amino-1-(naphthalen-1-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0224] Following the same procedure as in Example 4, starting from the nitrile described in Example 63 (1.44 g, 7.9 mmol), the title compound (2.46 g, 4.8 mmol) was obtained in a yield of 61%.1 H NMR(400MHz,DMSO-d6)δ8.02-8.05(m,3H),7.52-7.63(m,2H),7.42(m,1H),7.08(d,1H),5.41 (d,2H),4.55-4.72(m,6H),4.44(t,1H),3.18-3.82(m,13H),3.08-3.16(dd,2H),1.59(s,2H).

[0225] Example 65 (Compound 22)

[0226] (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(naphthalen-1-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol

[0227] Following the same procedure as in Example 2, starting from the amine described in Example 64 (2.46 g, 4.8 mmol), the title compound (1.16 g, 1.7 mmol) was obtained in a yield of 36%. 1 H NMR(400MHz,DMSO-d6)δ7.99-8.04(m,3H),7.54-7.66(m,2H),7.43(m,1H),6.75-7.25(m,4H),6.52(d,1H),5.91(s,2H),5.49 (s,1H),5.41(d,2H),4.71-4.80(m,6H),4.54(t,1H),3.20-3.88(m,13H),2.91-3.22(m,3H),2.52-2.63(dd,2H),1.11(d,3H).

[0228] Example 66: In vitro enzyme level inhibition experiment

[0229] According to the reference "Shao Y, Huang M, Cui W, et al. Discovery of a phosphodiesterase 9A inhibitor as a potential hypoglycemic agent [J]. J. Med. Chem., 2014, 57, 10304-10313", Tadalafil was used as a PDE5 positive control drug. A 20mmol / L Tris / HCl buffer (PH = 7.5), 10mmol / L MgCl2, 1mmol / L DTT and 10-30mmol / L specific fluorescent substrate were added. 3 H-cAMP or 3 H-cGMP (20000-30000 c.pm / assay, GE Healthcare) assay buffer and the test compound were incubated at room temperature (25°C) for 15 min. 0.2 mol / L ZnSO4 was added to terminate the reaction. The reaction product was quenched with 0.2 mol / L Ba(OH)2 3 H-AMP or 3 H-GMP precipitates and does not react 3 H-cAMP or 3 H-cGMP remained in the supernatant. The radioactivity of the supernatant was measured by liquid scintillation counting. 50 For the determination of the compound under test, at least 8 different concentrations were used. Each measurement was repeated at least 3 times. The IC 50 value.

[0230] Using the above method, the results of in vitro enzyme inhibition of the target compounds are shown in Table 1. As can be seen from Table 1, all 22 compounds have a certain inhibitory effect on PDE5 (<10 μmol·L -1 ), after comparison, it was found that compounds 12, 13, 16 and 20 (grey) had better inhibitory effects on PDE5 than other compounds (corresponding to the four most preferred ones in the text).

[0231] Table 1 In vitro enzyme level inhibition results of compounds on PDE5 注

[0232]

[0233] Note: The results are the average of three parallel experiments.

[0234] The above content is a detailed description of the preparation and application of the present invention in combination with specific preferred embodiments, but it cannot be considered that the specific implementation of the present invention is limited to these descriptions. For ordinary technicians in the technical field to which the present invention belongs, without departing from the preparation ideas and application directions of the present invention, several simple deductions and substitutions can be made, which should be regarded as belonging to the protection scope of the present invention.

Claims

1. A gentiobioside compound derived from a piperonyl ring, characterized in that: The general structural formula of the compound is: Wherein: A is selected from CH or N; B is selected from CR or N; R is selected from H, CH3, F, Br, Cl, NO2, NH2, OCH3, CN or CF3; X is selected from O, NH, CH=CH or NH-CH2, Y is selected from O-CH2, CH2-CH2, CH=CH, CH=N, N=N and N=CH; Also included are pharmaceutically acceptable salts, solvates and prodrugs of the above compounds; For compound I: For compound II: According to the difference between X and Y, the ring where XY is located can be divided into five-membered ring and six-membered ring, including aromatic ring and non-aromatic ring, and there is no four-membered ring.

2. The gentiobioside compound derived from piperonyl ring according to claim 1, characterized in that: For compound I: A is selected from CH or N, B is selected from CR or N; if A is N, then B is CR and R is H.

3. The gentiobioside compound derived from piperonyl ring according to claim 1 or 2, characterized in that: Compound I: R is selected from H, CH3, Br, Cl, NH2 and OCH3.

4. The gentiobioside compound derived from piperonyl ring according to claim 1, characterized in that: For compound II, X is selected from O, NH or CH=CH.

5. The gentiobioside compound derived from piperonyl ring according to claim 1 or 4, characterized in that: For compound II: Y is selected from O-CH2, CH=CH and N=CH.

6. The gentiobioside compound derived from piperonyl ring according to claim 1, characterized in that: The compound is selected from (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(4-fluorophenyl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(4-(trifluoromethyl)phenyl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(1H-indazol-6-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3R,4S,5S,6R)-2-((1R)-1-(benzo[d][1,3]dioxol-5-yl)-2-((1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3R,4S,5S,6R)-2-((1R)-2-((1-((Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(1H-benzo[d]imidazol-6-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(naphthalen-2-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3R,4S,5S,6R)-2-((1R)-2-((1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)-1-(naphthalen-1-yl)ethoxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol.

7. Use of the gentiobioside compound derived from the piperonyl ring according to any one of claims 1 to 6 in the preparation of phosphodiesterase-5 inhibitor drugs.

8. Use of the gentiobioside compound derived from piperonyl ring according to claim 7 in the preparation of phosphodiesterase-5 inhibitor drugs, characterized in that: The phosphodiesterase-5 inhibitor is selected from drugs for inhibiting male sexual dysfunction, erectile dysfunction ED, male impotence and premature ejaculation PE, pulmonary hypertension, inhibiting the increase of blood sugar caused by alloxan, anticoagulation, emotional instability or sleep disorders.

9. Use of the gentiobioside compound derived from piperonyl ring according to claim 7 in the preparation of phosphodiesterase-5 inhibitor drugs, characterized in that: The phosphodiesterase-5 inhibitor is selected from drugs for inhibiting male sexual dysfunction, erectile dysfunction ED, male impotence and premature ejaculation PE, poor sexual desire, difficulty in sexual arousal or orgasm disorder.

10. A pharmaceutical composition, characterized in that: The invention comprises the gentiobioside compound derived from the piperonyl ring according to any one of claims 1 to 6 and a pharmaceutically acceptable salt, diluent or carrier thereof.

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